Exoskeleton-based exercises for overground gait and balance rehabilitation in spinal cord injury: a systematic review of dose and dosage parameters

Background Exoskeletons are increasingly applied during overground gait and balance rehabilitation following neurological impairment, although optimal parameters for specific indications are yet to be established. Objective This systematic review aimed to identify dose and dosage of exoskeleton-based therapy protocols for overground locomotor training in spinal cord injury/disease. Methods A systematic review was conducted in accordance with the Preferred Reporting Items Systematic Reviews and Meta-Analyses guidelines. A literature search was performed using the CINAHL Complete, Embase, Emcare Nursing, Medline ALL, and Web of Science databases. Studies in adults with subacute and/or chronic spinal cord injury/disease were included if they reported (1) dose (e.g., single session duration and total number of sessions) and dosage (e.g., frequency of sessions/week and total duration of intervention) parameters, and (2) at least one gait and/or balance outcome measure. Results Of 2,108 studies identified, after removing duplicates and filtering for inclusion, 19 were selected and dose, dosage and efficacy were abstracted. Data revealed a great heterogeneity in dose, dosage, and indications, with overall recommendation of 60-min sessions delivered 3 times a week, for 9 weeks in 27 sessions. Specific protocols were also identified for functional restoration (60-min, 3 times a week, for 8 weeks/24 sessions) and cardiorespiratory rehabilitation (60-min, 3 times a week, for 12 weeks/36 sessions). Conclusion This review provides evidence-based best practice recommendations for overground exoskeleton training among individuals with spinal cord injury/disease based on individual therapeutic goals – functional restoration or cardiorespiratory rehabilitation. There is a need for structured exoskeleton clinical translation studies based on standardized methods and common therapeutic outcomes. Supplementary Information The online version contains supplementary material available at 10.1186/s12984-024-01365-2.


Introduction
Over the past decade, lower limb robotic technologies have been increasingly applied in neurorehabilitation [1,2].Essentially anthropomorphic in concept, these powered mechanical devices are used for locomotor training [3] and are classified as end-effectors or exoskeletons [4].The first one generates movements from the distal segment through a haptic interface [5], while the latter encompass independent robot joints guided in a pre-programmed trajectory which is further classified as unilateral or bilateral [4].Among such technologies, exoskeletons are reportedly useful to promote mobility in individuals with locomotor dysfunction, including those with complete lower extremity paralysis [6].Exoskeletons often do so through motorized actuators that assist hip, knee, and ankle motion in dynamic orthoses capable of supporting, stabilizing and reciprocally progressing the lower limbs [4].Newer generation devices offer training modes which allow therapists to manually trigger and control steps, in addition to adaptive and variable assistive features for individuals with incomplete injuries and a fair prognosis for voluntary active movement and functional recovery.
In terms of motor support, exoskeletons offer different types of assistance including active (equipment performs the movement, partially or totally, through powered assistance to the user); passive (device does not offer powered assistance to the movement, users execute by themselves); active-assisted (offers powered assistance to complete movements initiated by the user); resistive (offers resistance to movements initiated by the user); and interactive (uses feedback to correct movements based on interactions between actuators and control strategies) [4,7,15].Understanding these different levels of assistance is important to account for the variable forms of haptic feedback involved in robotic motor training which can either enhance or degrade motor performance depending on the patient's impairments and abilities (e.g., novice learners vs. advanced learners, subacute vs. chronic patients, those with autonomic or sensory function, presence or absence of spasticity, etc.) [16].Prior publications with these variable assistive devices have shown that gait and balance training with exoskeletons contribute to increased energy expenditure, muscle activation/recruitment and weight bearing [17][18][19][20], in addition to improved independence and health-related quality of life [21].These outcomes are often achieved in response to neurorecovery fostered by functional restoration programs [22].Functional Restoration interventions focus on the refinement of sensorimotor function in daily living.That ability is associated with the stimulation of remaining neural connections that even in SCI/D re-enable sensorimotor function following repeated exposure to directed stimuli, hence yielding [23] greater motor and autonomic recovery [23,24].
Specific to SCI/D, a recent study of exoskeleton-based rehabilitation among individuals with subacute injury reported that exposure to sixteen 30-min sessions of robotic-assisted gait training led to a significant improvement in gait as measured by the Walking Index SCI II (WISCI-II), which translates to more functional gait and activities of daily living [25].Moreover, Tamburella et al. [26] reported that individuals living with SCI/D could walk significantly faster, with longer steps and reduced gait cycles after rehabilitation with a powered exoskeleton.Similarly, Okawara et al. [27] reported gains in the 10-Meter Walk Test (10MWT), Time Up and Go (TUG) and Berg Balance Scale (BBS) after twenty 60-min sessions of body weight supported treadmill training (BWSTT) with a hybrid-assisted limb system.These results, however, were only observed in SCI/D patients with prior high walking ability as measured by the WISCI-II.In a similar population, Baunsgaard et al. [28] performed twenty-four 60-min sessions of robotic exoskeleton gait training, which resulted in improvements in the 10MWT, TUG and BBS, however with no treadmill or body weight support.The aforementioned results suggest that individuals living with subacute spinal cord lesions (< 1 year) are most likely to experience therapeutic benefits.However, individuals living with chronic SCI/D may also benefit from these interventions.While neuroplasticity is primarily expected at earlier phases after SCI/D, improvements are still attainable at later stages, specifically in response to coordinated, repeated motor stimuli as fostered by exoskeletons [4,17,28].
In response to the growing interest in exoskeletons to enhance the outcomes of neurorehabilitation, particularly in SCI/D, a significant body of literature has been published on associated topics and therapeutic benefits such as cardiovascular function [19], gait performance and training [17,19], spasticity and pain [18], device characteristics [29], cardiorespiratory function and fatigue [30].Although the aforementioned evidence is based on structured rehabilitation protocols, little emphasis has been given to discussing dose and dosage parameters of the exercises used in the respective therapeutic protocols beyond feasibility, safety and the specific outcomes observed.Additionally, interventions using powered exoskeleton-based rehabilitation for gait and balance were reportedly delivered under widely variable designs [31][32][33][34].Although dose and dosage parameters were reported by previous systematic review authors in adults with SCI/D who underwent lower limb powered exoskeleton rehabilitation for overground gait and balance, most did not discuss these training parameters.Instead, most authors acknowledged the absence of best practice recommendations in the field and endorsed the need to further understand rehabilitation designs aimed to restore or maintain locomotion with powered exoskeletons [7,15,21,35].
This systematic review addresses two main questions: (1) To what extent are dose (e.g., single session duration, and total number of sessions) and dosage (e.g., frequency of sessions per week, and total duration of the intervention) of exoskeleton-based exercises reported in the literature on overground gait and balance rehabilitation for adults with SCI/D (subacute or chronic, complete or incomplete)?; and, ( 2

Methods
This systematic review was conducted in accordance with the Preferred Reporting Items Systematic Reviews and Meta-Analyses (PRISMA) guidelines [36] and registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42022319271.

Search strategy and data sources
The search strategy was co-developed by the authors in collaboration with a local Medical Librarian and Information Specialist (MP) using the concepts contained in the PICO framework encompassing Population, Intervention, Comparisons, and Outcomes.Valid subject headings for each database were utilized as appropriate, as were free text terms pertinent to each topic or concept (e.g., Spinal Cord Injuries; Paraplegia; Quadriplegia; Exoskeleton Device; Gait; Postural Balance).The search was performed from inception to 31 March 2022 using five electronic databases: CINAHL Complete (EBSCOhost), Embase (Ovid), Emcare Nursing (Ovid), Medline ALL (Ovid; includes PubMed non-Medline records), and the Web of Science Core Collection.Each concept searched was kept as broad as possible to ensure all relevant materials were identified.The Population encompassed adults with Spinal Cord Injuries.The Intervention was the use of Exoskeletons.The Outcomes included any biomechanical and/or clinical measures related to Gait or Balance.No date or language limits were applied.The full Medline search strategy is shown in Additional file 1.

Study selection criteria
Studies were included according to the following criteria:  1.

Screening criteria and study selection
After the initial search, duplicate manuscripts were excluded, and remaining references were imported into the Covidence Systematic Review Manager (Veritas Health Innovation Ltd, Australia).Articles eligible for title and abstract screening were assessed by PN and WHS independently (a third author, KEM, was assigned to resolve eventual conflicts).Prior to working independently, an initial fidelity agreement regarding the article inclusion/exclusion process was established based on the first 10 studies with a 100% agreement between raters.If titles and abstracts did not report enough information to determine article inclusion or exclusion, the full text was screened.Following the title and abstract screening, remaining citations were independently read in full by the same two authors to verify articles met inclusion criteria.Again, disagreements were resolved by the same third author.

Data charting and analysis
The authors created individual versions of a data extraction form.Their forms were compared and merged into a combined form used to abstract data from the included manuscripts.The data extraction form was pilot tested by two authors (PN and WHS), who independently extracted data from two of the included manuscripts.Following a comparison of the outcomes obtained, minor revisions were implemented towards a final, revised version of the abstraction form.Data were extracted from the selected papers about authors; year of publication; institution and country of the study; participant demographics (age, number of participants, etiology and level of lesion,); dose (e.g., total number of sessions, and duration of each session, in minutes) and dosage (e.g., frequency of sessions per week, and duration of the complete intervention, in weeks); gait and balance outcomes measures (e.g., Mini-Balance Evaluation Systems Test, Community Balance & Mobility Scale, ABC Scale, 6MWT, 10MWT, BBS, TUG, gait speed).The data were synthesised by the authors and reported in tables and graphics.Narrative syntheses were applied.
In the case of articles with missing data (e.g., total duration of intervention), the corresponding author was contacted by e-mail.For some studies included, dose and dosage parameters were not explicitly stated, but could be estimated using available training parameters in the published article.For instance, sessions per week multiplied by the number of intervention weeks informed the total number of sessions; total number of sessions divided by weeks informed weekly frequency; and total number of
Overall, considering the dose and dosage parameter averages across all studies included in this review, regardless of clinically relevant change, a protocol with 60-min individual sessions, 3 times a week, for 9 weeks is suggested for a total of 27 sessions.The mean and standard deviation, or median and interquartile range for overall interventions and for protocols focused on specific therapeutic intent (e.g., functional restoration or cardiorespiratory rehabilitation) are described in Table 3.As for the total number of sessions and the duration of interventions recommended, most studies showed variability within a range of (24-36 sessions) and (8-12 weeks), respectively [6,28,44,47,49,51,52,54].Also, the duration of each session (60-min) and weekly frequency (3 times a week) were mostly consistent across the reviewed dataset, including studies with clinically relevant changes [6, 28, 42-49, 51, 52, 54, 56].

Protocol therapeutic intent
The studies included in this systematic review of overground exoskeleton training dose and dosage were classified in two groups according to the inferred therapeutic intent based on the described study design which addressed: functional restoration [6, 44-47, 49-53, 56-58] or cardiorespiratory rehabilitation [41-43, 48, 54, 55].The therapeutic intent was determined based on each study's primary research question, aim and main

Functional restoration
Thirteen (n = 13) studies focused on functional restoration [6, 44-47, 49-53, 56-58].Of those, eleven reported statistically significant improvements and/or showed improvements equal or higher than the MCID for gait and/or balance outcome measures [6, 28, 44-47, 49-52, 56].Table 4 summarizes the individual studies' aims and main results.The functional restoration protocols ranged from 10 to 51.5 sessions, 2 to 5 sessions a week, 3 to 12 weeks of duration for 45-to 90-min.Considering the studies with significant motor improvement (n = 11), it is suggested that a protocol aimed towards functional restoration would encompass 60-min individual sessions carried 3 times a week, over 8 weeks for a total of 24 sessions (Table 3).Functional restoration interventions were shorter than cardiorespiratory interventions.They included subacute or chronic SCI/D patients, mostly with complete or incomplete thoracolumbar lesions.In this group analysis,  two manuscripts did not report improvements [53,57].The first one [53] reported the effects of a new robotic exoskeleton based on ten 30-min sessions over 2 weeks, that is shorter than the period suggested by our recommendation based on studies with significant functional restoration gains.The second study [57] focused on describing the protocol performed in a rehabilitation research institute, including the process of participant recruitment, fitting, donning, standing, standing balance, walking, mobility training, sitting and doffing.The functional outcomes, however, were measured only after the intervention.Additionally, among the respective study participants, individuals underwent 12 to 102 sessions over 4 to 34 weeks in remarkably variable study designs.Regarding the therapeutic content, studies on functional restoration mainly focused on sit to stand, and stand to sit transitions, standing balance and walking training for significant changes or improvements above the MCID as per functional restoration outcome measures.The frequency of training, total number of trainings, therapy content (exercise training) and studies with significant changes are shown in Table 5.A.

Cardiorespiratory rehabilitation
The six studies (n = 6) focused on cardiorespiratory rehabilitation [41-43, 48, 54, 55] showed significant improvement of cardiorespiratory function.Table 6 summarizes the cardiorespiratory studies' aims and main results.Cardiorespiratory-centered interventions ranged from 16 to 72 sessions, 2 to 5 sessions weekly, for 4 to 24 weeks.Individual sessions lasted between 55 to 90 min.Because the six protocols yielded significant improvement in cardiorespiratory function, it is suggested that interventions to that end are likely to succeed when based on 60-min sessions carried 3 times a week for 12 weeks in a total of 36 sessions (Table 3).
Unexpectedly, protocols focusing on cardiorespiratory outcomes were longer in average than protocols for functional restoration.Conversely, four of the referred articles also reported significant improvements in gait and balance measures [42,48,54,55], while two manuscripts reported improvements in cardiorespiratory outcomes alone [41,43].The latter studies were based on 16 sessions over 4 weeks [41] and 17 sessions over 9 weeks [43], indicating that shorter interventions could be enough to improve cardiorespiratory function alone, that is uncoupled from significant functional restoration.In this case, the cardiorespiratory recommendation would include 60-min sessions carried out 3 times a week for 6 weeks for a total of 18 sessions.
Regarding the therapeutic content, studies on cardiorespiratory rehabilitation mainly focused on walking training and sit to stand and/or stand to sit transitions for significant improvements in cardiorespiratory outcome measures.The frequency of training, total number of trainings, therapy content and studies with significant changes in cardiorespiratory parameters are shown in Table 5.B.

Discussion
This review aimed to identify the dose and dosage parameters of exoskeleton-based exercises for overground gait and balance training in individuals with SCI/D.Although previous studies have discussed this topic in different neurological populations [7,62], to the best of our knowledge, this is the first review to prioritize the investigation and discussion of dose and dosage of overground exoskeleton therapy among individuals with SCI/D -a need repeatedly acknowledged in recent literature [7,15,21,35] yet widely overlooked as a primary research topic.We have summarized evidence from 19 manuscripts to determine current training parameters for specific therapeutic indications to inform best practice recommendations in exoskeleton-based SCI/D rehabilitation.Of 19 manuscripts, seventeen [6,28,[41][42][43][44][45][46][47][48][49][50][51][52][54][55][56] reported statistically significant improvements and/or gains above the MCID in the gait, balance, cardiorespiratory and/ or related physiological outcomes they assessed.The evidence gathered supports the assumption that exoskeletons are a promising therapeutic tool in SCI/D, particularly for functional restoration [6, 28, 44-47, 49-52, 56] and/or cardiorespiratory improvement [41-43, 48, 54, 55].

Protocol design
Based on strict adherence to the systematic review inclusion criteria, several manuscripts initially screened did not fully report dose (total number of sessions, and duration of the session) and dosage (frequency per week, and duration of the intervention) parameters and were excluded.Consistent with previous reviews [35,62] on exoskeleton-based gait rehabilitation the lack of dose and dosage parameters ultimately limits the replication and generalizability of the outcomes reported.The absence of dose and dosage information also limits the translation of findings to evidence-based clinical practice, whereas the requirement for routine universal reports of dosing parameters in future studies would foster knowledge dissemination and implementation of precision rehabilitation approaches in the field.To support the development of future studies with structured information for better clinical translation, a checklist for reporting exoskeleton therapy is proposed in Table 7.

Protocol effectiveness
Training effectiveness (e.g., changes in assessment values at or above the MCID) is shaped by multiple factors beyond dose and dosage, including but not limited to device parameters and the extent or intensity of training.Relative to exoskeleton-based gait and balance rehabilitation such factors include device assistance and resistance levels, different walking patterns (e.g., step and stride length, width of base of support, gait speed and step cadence) as well as exercise intensity.The latter is associated with a lack of specific consensus-based measures and definitions universally adopted by experts in the field of neurorehabilitation [63].This is particularly true in the SCI/D populations among whom there is substantial heterogeneity in neurological impairment, and associated variability in prognosis and responsiveness to exoskeleton interventions.As a result, variability in prognosis and responsiveness are commonly observed and personalized prescriptions are provided in the absence of consensusbased terminology and practices [64,65].In this context, the best practice recommendations derived from this systematic review are valid given the reporting of whether the participants achieved a clinically meaningful change in function/assessment parameter based on the dose and dosage reported despite the lack of data specifying exercise intensity.Despite protocol variability, including that of device choice, therapeutic intent, and training intensity, it is possible that the significant changes reported are associated with the repeated exposure to active standing time versus non-active sitting time [65].However, most studies included similar functional therapeutic activities (e.g., sit to stand transitions, standing and balance training and walking training).In fact, exercise intensity in robotic rehabilitation, although not standardized, is often associated with the number of repetitions (e.g., step count), step frequency and total walking distance.The modulation of intensity on a case-by-case basis likely favored the observed performance improvements across the multiple protocol designs reported in this review.Future studies reporting the therapeutic benefits of exoskeleton therapy should include the therapeutic indication, device choice and parameters, exercise intensity, and the dose and dosage parameters as means to improve precision rehabilitation -particularly among people living with a spinal cord impairment and multimorbidity [66].

Injury characteristics
In addition to exercise parameters, the influence of injury characteristics on exoskeleton-based SCI/D rehabilitation is very likely, yet controversial.Benson et al. [67] reported that individuals with complete injuries showed greater improvement in walking speed than incomplete injured pairs.That may be because participants with incomplete lesions were functional walkers before the beginning of their training, benefiting mostly from the ability to walk longer distances with exoskeletons as opposed to participants with complete injuries to whom exoskeletons allowed not only orthostatism, but gait initiation and speed improvements.In agreement with those findings, Xiang et al. [53] reported that individuals with higher spinal lesions and motor complete injuries showed greater improvement in gait and functional outcomes (gait speed and 6MWT) while using exoskeletons compared to people who were functional walkers with lower and or incomplete lesions.Conversely, it has been reported that adults living with lower neurological level of injury (complete versus incomplete) can achieve significantly faster walking speeds following exoskeleton training [6,68,69].The explanation of these findings may be linked to the fact that people with complete SCI/D obtain more remarkable gains with training (e.g., from no standing to walking), although they still walk slower than individuals with incomplete lesions [53,67].Differences in gait speed is possibly associated with the remaining neural pathways in individuals with incomplete lesions, which foster better neurorecovery in response to functional restoration strategies [2].This assumption agrees with Louie et al. 's [17] report that walking speed with exoskeletons is positively correlated with the level of spinal injury (coded from 0 (cervical) to 17 (lumbar)) and training duration.Thus, lower injuries and longer training could, favor greater locomotor gains for individuals with SCI/D.Nevertheless, Sale et al. [50] reported that exoskeleton rehabilitation is safe and feasible across a heterogeneous sample of persons with SCI/D provided it is tailored to their personal needs.Further, it is plausible that there may be additional therapeutic benefits of longitudinal training not addressed in this review.

Exoskeleton-based therapeutic intent and physiological considerations
Upon review of the nineteen manuscripts included, consistent similarities across some of the protocols in terms of their therapeutic goals led us to classify the studies in two categories of therapeutic intent (e.g., functional restoration and cardiorespiratory rehabilitation).While the clinical purpose of individual studies seemed distinguishable enough for us to categorize them, that was not explicitly disclosed by the authors.The current knowledge of the physiological mechanisms involved in exoskeleton-based therapies remains limited.A prior review reported that neurophysiological responses in exoskeleton recovery are linked to the exploitation of neuroplasticity, sensory stimulation, and coordination of limb and muscle activation during the training.The authors purport that functional restoration and neurorecovery are much like a relearning process where preserved sensorimotor and neural circuits are engaged to promote recovery [2].For cardiorespiratory function, exoskeleton gait training's rationale for the observed improvements in function associated with stimulation of the cardiorespiratory system and activation of the lower limbs is due to an increase in metabolic rate indicating this is an effective way of increasing energy expenditure with consequent improvements of cardiorespiratory fitness.Moreover, exoskeleton training contributes to the augmentation of end-systolic and enddiastolic volume, cardiac output, ventricular mass and reduces heart rate following cardiovascular conditioning [42,54,70].
Our findings suggest that different exercise exposures are needed to achieve MCID as per therapeutic intent in SCI/D rehabilitation, with cardiorespiratory changes demanding longer protocols compared to functional restoration.Nevertheless, we hypothesized that shorter interventions would be warranted for cardiorespiratory gains due to faster cardiovascular adaptation to structured exercises compared to neurological responses [71,72].This unexpected outcome may be related to two cardiorespiratory-focused manuscripts in which participants underwent longer interventions (72 [42] and 60 [48] sessions) to evaluate changes over the time (early, mid and late changes), justifying the longer experimental designs.Additionally, of the six studies [41-43, 48, 54, 55] included in cardiorespiratory rehabilitation, two [41,43] had significant improvement in cardiorespiratory function but not in gait, which was achieved with shorter interventions, in line with our initial hypothesis.Supporting our hypothesis, Faulkner et al. [73] reported that exoskeleton gait training associated with conventional physiotherapy in 5 sessions over a single week improved cardiovascular health, by reducing the augmentation index and mean arterial pressure.Further, Evans et al. [42] reported statistically significant increases in cardiovascular efficiency as early as 6 weeks after exoskeleton gait training.Interestingly, despite protocol duration variability, the six articles focused on cardiorespiratory training reported significant improvements in cardiorespiratory health as per increased oxygen consumption, heart rate and metabolic equivalent, in addition to reduced perception of effort and oxygen cost [41-43, 48, 54, 55].A prior systematic review reported that exoskeleton gait training elevates the energy expenditure, while allowing participants to exercise at moderate intensity, further indicating exoskeletons are beneficial for cardiorespiratory training [19].
In SCI/D, reduced lower-limb weight bearing and other health complications contribute to the loss of muscle mass and bone mineral density (BMD), specially below the level of injury [74].This leads to an increased risk of fragility fractures, which should be accounted for when performing exoskeleton-based gait training.That is important due to previous reports of lower limb fragility fracture after exoskeleton use, mainly induced by the effect of gravity and pressure points created by the resistance of the equipment against the user's body [75,76].Thus, people living with SCI/D should be advised of their fracture risk, prior to using wearable exoskeletons for increased safety, regional improvements in bone strength and BMD [59].To prevent fragility fractures, Bass et al. [59] developed a volume and progression algorithm based on BMD thresholds.Accordingly, individuals with osteoporotic profile (T-score ≤ -2.5) should be exposed to a slow-progression program, individuals with osteopenic profile (-2.5 < T-Score < -1.0) should start with moderate-progression and individuals with preserved BMD profile (T-Score ≥ -1.0) should be enrolled in a fastprogression walking program.It is worth noting that as per the position statement 4 in the International Society for Clinical Densitometry, there is no established threshold BMD value below which weight-bearing activities are absolutely contra-indicated, and that BMD and clinical risk factors should be used together on a case-to-case basis to assess risk exposure [74].Furthermore, people living with SCI/D are in a higher risk of developing skin abrasions and tissue injury [77].Many studies have reported skin abrasions after the use of exoskeleton in SCI/D population [44,53,56,58].The reduction of physical activity levels, immobilization, changes in circulation and microcirculation, sensory loss, skin compression due to positioning and impaired venous return are aspects of injury that preclude individuals to lower extremity abrasions [77,78].Also, participants with sensory impairment are at greater risk of developing skin lesions [79], and hence warrant ongoing screening for skin integrity.That is particularly true at points of higher pressure caused the interface between the skin and the exoskeleton [44,58,79].

Considerations for translation to practice
Recommendations from systematic reviews are extremely helpful at informing new research designs and guiding the translation of optimal evidence-based findings to clinical practice.However, it is also true that best practice recommendations, as identified by this review cannot always be implemented, particularly considering contextual disparities, including different countries (e.g., North America, Europe and Asia, Fig. 2), devices and therapeutic intent.Should a clinician find the implementation of the suggested best practice recommendations infeasible, reproducing the observed dose and dosage of therapy with a specific device can be limited to the shortest study with reported clinical effectiveness above the MCID for the outcome of interest (see the reduced dose and dosage but observed MCID with specific interventions on Table 5).For instance, ten 60-min sessions at a frequency of 5 sessions per week over two weeks yielded significant improvements in functional restoration [46].Alternatively, sixteen 50-60-min sessions at a frequency of 4 times a week over four weeks yielded significant improvements in cardiorespiratory function [41].We also suggest that patients be supported to work incrementally with healthcare providers to further implement best practice dose and dosage recommendations.

Study limitations
This study has limitations that include the relatively scarce literature available, which did not allow us to analyze the results according to the participant's characteristics (sex, ASIA Impairment Scale, neurologic level of injury, etc.).However, the population described in this review are similar to those described in prior reviews among individuals living with SCI/D [17,62].Also, it is important to state that the implementation of exoskeleton-based interventions is still limited due to the cost, availability of the equipment, equipment specifications and limitations, and the lack of highly trained staff to support exoskeleton-based therapy [80][81][82].As for the limited study sample size, our search was broadened to identify manuscripts applying overground exoskeletons in SCI/D, but many of the identified references did not fully report dose and dosage -that is at least 3 parameters -and were excluded in a strategy that reduced the already restricted sample, but guaranteed data consistency.Additionally, the references included in this systematic review were classified according to their clinical intent by the review authors, which may not reflect the original authors' intent.Furthermore, the study quality and risk of bias were not assessed as our search aimed to perform a comprehensive overview of dose and dosage in exoskeleton gait and balance training in SCI/D.Nevertheless, this systematic review is consistent with prior reports in the literature that did not report risk of bias in studies involving exoskeleton rehabilitation [7,21,35,62].The exoskeleton device donning and doffing times were inconsistently reported across the reviewed studies, with only two of them [6,44] indicating that donning and doffing times were not part of the reported session duration and a single study [43] indicating that the session duration included donning and doffing.While we believe that some of the other sixteen studies included donning and doffing times in the session duration, we presume that most studies reported the time dedicated to standing/walking training apart from donning and doffing.Altogether, we encourage readers to implement the enclosed practice recommendations and to report device donning and doffing times, device parameters and therapeutic intensity in future reports.We also encourage clinicians and investigators to describe barriers and facilitators to implementation of best practices in different contexts.

Conclusions
In summary, this systematic review advances the understanding of overground exoskeleton-based gait and balance training in SCI/D and its role in facilitating functional recovery and or cardiorespiratory fitness.The review results provide evidence-based clinical practice recommendations, which are tailored to the therapeutic intent of the intervention.However, problems with inconsistent reporting of exoskeleton training dose and dosage and the heterogeneity of study designs among adults with SCI/D preclude fulsome dissemination of data and are acknowledged as important limitations.To advance the field of exoskeleton rehabilitation in SCI/D and increase research quality, there is an urgent need to standardize clinical practice recommendations and guidelines through well-structured studies with clear indications of their therapeutic intent.Finally, we highlight the need for multicentre studies, which could validate the therapeutic effectiveness of specific dose and dosage parameters for optimal gait and balance rehabilitation among adults with SCI/D based on poling of data from multiple sites and contexts.
) Which outcome measures are used to inform changes in gait and balance following exoskeleton-based rehabilitation in SCI/D?We hypothesized that the investigation of dose and dosage parameters of exoskeleton-based exercises reported from interventions for overground gait and balance rehabilitation interventions among individuals with SCI/D would contribute to: (1) the identification of consistent dose and dosage parameters to inform best practice recommendations related to locomotor rehabilitation strategies; and, (2) informing the development of innovative, clinically robust protocols evaluating exoskeletons for SCI/D rehabilitation; and, (3) to driving implementation of exoskeleton based training programs within tertiary SCI/D rehabilitation settings.

Fig. 2
Fig. 2 Frequency of study per country.Figure represents the country of origin of 18 of the 19 studies included because 1 study was a multicenter study across Europe assistance) Sit to stand, walking and climbing stairs reaching 40-60% of maximal heart rate 6MWT, Borg (RPE), LEMS, FEV1, FEF25, FEF50, FEF75, PEF, MVV Yes with a robotic exoskeleton and to assess the changes in cardiorespiratory responses to robotic exoskeleton-assisted overground walking training 6MWT increased at mid and post-training.Oxygen cost reduced along the training Xiang et al. 2021, J Neuroeng Rehabil, v. 18 Aimed at finding out whether the EAW trainings are different from conventional rehabilitation trainings in improving pulmonary function parameters among SCI individuals Significant improvement in pulmonary function for exoskeleton group.

Table 1
Inclusion and exclusion criteria 6MWT 6-min walk test, 10MWT 10-m walk test, BBS Berg Balance Scale, TUG Time Up and Go, WISCI Walking Index for Spinal Cord Injury

II Inclusion criteria Exclusion criteria
mine distribution the Shapiro-Wilk Test was used considering p < 0.05 as non-normal distribution.

Table 3
Summary means and standard deviations and medians and interquartile ranges of exoskeleton protocols in adults with spinal cord injury a : median (interquartile range); b : mean (standard deviation) Fig. 3 Frequency of clinical outcomes reported.Heat map presenting the frequency of clinical outcomes measures reported, per studies by manufacturer.%HRR percentage of heart rate reserve, CO2 carbon dioxide, FEF forced expiratory flow, FEV1 forced expiratory volume in 1 s; LEMS Lower Extremities Motor Score, MVV maximum voluntary ventilation, NASA-TLX NASA Task Load Index, NBD neurogenic bladder dysfunction, PCI Physiological Cost Index, PEF peak expiratory flow, PGI-I Patient Global Impression of Improvement; Resp.respiratory, RPE rating of perceived exertion, SCATS Spinal Cord Assessment Tool for Spastic Reflexes, SCIM-II Spinal Cord Independence Measure II, UEMS Upper Extremities Motor Score, VAS Visual Analogue Scale, WISCI-II Walking Index for Spinal Cord Injury II

Table 4
Summary of the aim and main results of studies focused on functional restoration in adults with spinal cord injury 10MWT 10 m walk test; 6MWT: 6-min walk test, BBS Berg Balance Scale, FES functional electrical stimulation, HAL Hybrid Assistive Limb; m meters, OG overground, OPLL ossification of the posterior longitudinal ligament, RAGT robotic assisted gait training; s: seconds; SCI spinal cord injury, TUG Time Up and Go

Table 5
Dose and dosage parameters, therapy content, outcome measures and effectiveness per study percentage of heart rate reserve; 6 min walk test; 10 m walk test; BBS Berg Balance Scale, BP blood pressure, BSC Bristol Stool Chart, CO2 carbon dioxide; FEF forced expiratory flow, FEV1 forced expiratory volume in 1 s, HR heart rate, HRV heart rate variability; LEMS Lower Extremities Motor Score, MET metabolic equivalent; MVV maximum voluntary ventilation, NA not available, NASA-TLX NASA Task Load Index, NBD neurogenic bladder dysfunction, NPSI Neuropathic Pain Symptom Inventory, PCI Physiological Cost Index, PEF peak expiratory flow; PGI-I: Patient Global Impression of Improvement; Resp.: respiratory, RPE rating of perceived exertion; SCATS Spinal Cord Assessment Tool for Spastic Reflexes, SCIM-II Spinal Cord Independence Measure II; SD standard deviation, TUG timed up and go, UEMS Upper Extremities Motor Score; VAS Visual Analogue Scale, WISCI-II Walking Index for Spinal Cord Injury II.*Donning and doffing time not included in session duration.** Donning and doffing time included in session duration; Bold: indicates successful studies by MCID or statistically significant change %HRR

Table 6
Summary of the aim and main results of studies focused on cardiorespiratory interventions in adults with spinal cord injury 30MWT 30-min walk test, 6MWT 6-min walk test, ABPI ankle brachial pressure index, ABT activity-based therapy, EAW exoskeleton-assisted walking, HR heart rate, KAFO knee-ankle-foot orthosis; LEMS Lower Extremities Motor Score, MET metabolic equivalent of task; RLT robotic locomotor training, VO2 oxygen consumption

Table 7
Suggested checklist of essential information to include when reporting exoskeleton-based rehabilitation